Effective Date

Date of Origin 

7/1/2023

Cerdelga®

(eliglustat)

Capsule

Long-term treatment of adult patients with Gaucher disease type 1 who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test for determining CYP2D6 genotype

Limitations of Use:

• CYP2D6 ultra-rapid metabolizers (URMs) may not achieve adequate concentrations of Cerdelga to achieve a therapeutic effect
• A specific dosage cannot be recommended for those patients whose CYP2D6 genotype cannot be determined (indeterminate metabolizers)

1

Zavesca®

(miglustat)*

Capsule

Monotherapy for treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g., due to allergy, hypersensitivity, or poor venous access)

* Generic available

2

Gaucher Disease

Gaucher disease (GD), the most common of the lysosomal storage disorders (LSDs), is a rare autosomal recessive metabolic disorder affecting only 1 in 40,000 in the general United States population.(4,7) Mutations in the GBA (glucocerebrosidase) gene cause reduced activity of the lysosomal enzyme glucocerebrosidase (also known as acid beta-glucosidase), resulting in the accumulation of harmful quantities of the glycolipid glucocerebroside (also known as glucosylceramide, or GLC) and other related sphingolipids. This multisystemic accumulation of GLC in various tissues, especially in lysosomes of macrophages, compromises the bone marrow, spleen, and liver, and less often the lungs, skin, kidneys, and heart.(3,4,7,8,9,10)

GD is classified into 3 clinical types, distinguished by their clinical features, management, and prognosis. However, as with most genetic diseases, there is a continuum of clinical findings and overlap within and between types, resulting in identification of additional subtypes.(4,5,7,9) GD Type 1 (GD1) is distinguished from GD Types 2 (GD2) and 3 (GD3) by the lack of characteristic involvement of the central nervous system (CNS).(3,4,5,7,8) As such, it is also known as non-neuronopathic GD.(3,4,7) In the United States, Europe, and Israel, 90% of GD patients have GD1, with a high carrier frequency in the Ashkenazi-Jewish population.(3,4,5,7,8) Age of onset for GD1 is variable, with some patients presenting between 12 and 24 months of age and others having no clinical signs until late adulthood.(3,4,7) Manifestation in the first or second decades of life typically results in more aggressive and severe symptoms than those manifesting at a later stage of life.(7) Presentation of symptoms among patients with GD1 is variable. Splenomegaly is the most common symptom; hepatomegaly is also common, but the liver increases relatively less than the spleen. Other common presenting symptoms are anemia, thrombocytopenia, bone disease, and delayed growth.(3,4,5,7,8,10) 

GD2 is an acute neuronopathic form of GD characterized by early onset, typically in the first year after birth. Neurologic complications are extensive and severe, with limited psychomotor development. Death occurs within the first 2 years of life, usually due to respiratory failure.(3,5,7) GD3 is the subacute or chronic neuronopathic form, has later onset than GD2, and has slower disease progression with patients typically surviving to second or third decades of life. The distinction between GD2 and GD3 is difficult.(3,4)

A diagnosis of GD should be considered in patients with unexplained anemia and easy bruising, particularly if they have enlargement of the spleen and liver.(3) Definitive diagnosis of GD can be confirmed by the finding of reduced glucocerebrosidase activity in leukocytes, fibroblasts, or other nucleated cells.(3,4,5,7,9,10) This enzyme assay test is typically known as BGL (beta-glucosidase leukocyte), and a finding of 15% or less of mean normal glucocerebrosidase enzyme activity is indicative of GD.(4,5) If BGL results are not conclusive and/or further confirmatory testing is desired, genetic testing is an option. Identification of two pathogenic alleles in the GBA gene can also determine diagnosis of GD.(3,4,5,9) The presence of neurologic complications has critical implications for prognosis and treatment and should be determined as soon as possible after diagnosis. Neuronopathic symptoms indicative of GD2 and GD3 include bulbar signs (e.g., stridor, strabismus, swallowing difficulty), pyramidal signs (e.g., opisthotonus, head retroflexion, spasticity, trismus), oculomotor apraxia, tonic-clonic seizures, myoclonic epilepsy, dementia, and ataxia. If not already performed as part of the diagnostic process, baseline measurement of hemoglobin level, platelet count, liver volume, and spleen volume should be documented.(4,5,7,10)

When possible, management of a patient with GD should occur with a multidisciplinary team at a Comprehensive Gaucher Treatment Center(5) (list of facilities nationwide available at www.gaucherdisease.org. Goals of treatment are elimination or improvement of symptoms, prevention of irreversible complications, and improvement in overall health and quality of life. An additional goal in children is optimization of growth.(3,6,8) Currently, two different therapeutic approaches for the treatment of GD1 are used: enzyme replacement therapy (ERT) [Cerezyme (imiglucerase), VPRIV (velaglucerase alfa), Elelyso (taliglucerase alfa)] and substrate reduction therapy (SRT) [Cerdelga (eliglustat), Zavesca (miglustat)].(3,5,6,8,9) ERT, intravenously administered, targets macrophages and increases the breakdown of accumulated glycolipids.(8) SRT, orally administered, reduces the amount of synthesized GLC to a level that can be effectively cleared by the mutated enzyme’s residual activity.(5,6,8)

The decision to offer ERT or SRT in patients with GD1 is based upon disease severity and/or significant disease progression.(6,7,8,10) To begin treatment with ERT or SRT, clinically significant manifestations must be present. Thrombocytopenia of sufficient magnitude to justify initiation of treatment is defined by platelet counts less than 100,000 microliter, as well as symptomatic presentation of splenomegaly, anemia, bone disease, and/or delayed growth.(3,4,5,7,8,9)

Efficacy

Until the FDA approval of the SRT Cerdelga in 2014, ERT was the mainstay of therapy in patients with GD1. A 12-month phase 3, open-label, noninferiority study (ENCORE) in 106 adults (18 years of age and older) with GD1, stable after greater than or equal to 3 years of ERT with Cerezyme or VPRIV, found Cerdelga noninferior to Cerezyme in maintaining stability of four component domains (i.e., hemoglobin level, platelet count, liver volume, spleen volume). A 9-month randomized, double-blind, placebo-controlled study (ENGAGE) in 40 treatment-naïve GD1 patients 16 years of age and older, demonstrated that treatment with Cerdelga led to greater improvements in spleen and liver volume, platelet count, and hemoglobin level compared to placebo. These findings provided Cerdelga its designation as first-line or maintenance therapy in adult patients with GD1.(1,5,6,8) 

The SRT Zavesca, approved in 2003, is indicated only for GD1 patients for whom ERT is not an option (e.g., due to allergy, hypersensitivity, or poor venous access). Studies of Zavesca have demonstrated significant reductions from baseline in liver and spleen volume, and a non-significant increase from baseline in hemoglobin level and platelet count.(2,5,6) 

Safety

Cerdelga (eliglustat) is contraindicated in the following patients based on CYP2D6 metabolizer status due to the risk of cardiac arrhythmias from prolongation of the PR, QTc, and/or QRS cardiac intervals:(1)

• Extensive metabolizers (EMs):
  • Taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor
  • Moderate or severe hepatic impairment
  • Mild hepatic impairment taking a strong or moderate CYP2D6 inhibitor
• Intermediate metabolizers (IMs):
  • Taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor
  • Taking a strong CYP3A inhibitor
  • Any degree of hepatic impairment
• Poor metabolizers (PMs):
  • Taking a strong CYP3A inhibitor
  • Any degree of hepatic impairment

Zavesca (miglustat) has no contraindications.(2)

1

Cerdelga prescribing information. Genzyme Corporation. July 2021.

2

Zavesca prescribing information. Actelion Pharmaceuticals US, Inc. August 2022.

3

National Organization for Rare Disorders (NORD) – Physicians Guides. Gaucher Disease. Available at: https://rarediseases.org/physician-guide/gaucher-disease/.

4

Hughes D, Sidransky E, et al. Gaucher Disease: Pathogenesis, Clinical Manifestations, and Diagnosis. UpToDate. Last updated August 2021. Literature review current through November 2022.

5

Pastores GM, Hughes DA. Gaucher Disease. July 2000 [Updated June 2018]. In: Adam MP, Ardinger HH, Pago RA, et al. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1269/.

6

Hughes D, Sidransky E, et al. Gaucher Disease: Treatment. UpToDate. Last updated August 2022. Literature review current through November 2022.

7

Martins AM, Valadares ER, Porta G, et al. Recommendations on Diagnosis, Treatment, and Monitoring for Gaucher Disease. J Pediatr. 2009;155(4):S10-S18.

8

Biegstraaten M, Cox TM, Belmatoug N, et al. Management Goals for Type 1 Gaucher Disease: An Expert Consensus Document from the European Working Group on Gaucher Disease. Blood Cells Mol Dis. 2018;68:203-208. 

9

Wang RY, Bodamer OA, Watson MS, et al. American College of Medical Genetics (ACMG) Work Group on Lysosomal Storage Diseases: Diagnostic Confirmation and Management of Presymptomatic Individuals. Genet Med. 2011 May;13(5):457-484.

10

Weinreb NJ, Aggio MC, Andersson HC, et al. Gaucher Disease Type 1: Revised Recommendations on Evaluations and Monitoring for Adult Patients. Semin Hematol. 2004;41(suppl 5):15-22.

Cerdelga

eliglustat tartrate cap

84 MG

M ; N ; O ; Y

N

Zavesca

miglustat cap

100 MG

M ; N ; O ; Y

O ; Y

Cerdelga

Eliglustat Tartrate Cap 84 MG (Base Equivalent)

84 MG

60

CAPS

30

DAYS

Zavesca

Miglustat Cap 100 MG

100 MG

90

CAPS

30

DAYS

Cerdelga

eliglustat tartrate cap

84 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Zavesca

miglustat cap

100 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Cerdelga

Eliglustat Tartrate Cap 84 MG (Base Equivalent)

84 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Zavesca

Miglustat Cap 100 MG

100 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has a diagnosis of Gaucher disease type 1 (GD1) AND
2. If the patient has an FDA approved indication, ONE of the following:
   1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
   2. The prescriber has provided information in support of using the requested agent for the patient’s age for the requested indication AND
3. The patient does NOT have any neuronopathic symptoms indicative of Gaucher disease type 2 or type 3 [e.g., bulbar signs (e.g., stridor, strabismus, swallowing difficulty), pyramidal signs (e.g., opisthotonos, head retroflexion, spasticity, trismus), oculomotor apraxia, tonic-clonic seizures, myoclonic epilepsy, dementia, ataxia] AND
4. ONE of the following:
   1. The patient has baseline (prior to therapy for the requested indication) glucocerebrosidase enzyme activity of less than or equal to 15% of mean normal in fibroblasts, leukocytes, or other nucleated cells OR
   2. Genetic analysis confirmed two (2) pathogenic alleles in the glucocerebrosidase (GBA) gene AND
5. The prescriber has assessed baseline (prior to therapy for the requested indication) status of hemoglobin level, platelet count, liver volume, and spleen volume AND
6. The patient has at least ONE of the following clinical presentations at baseline (prior to therapy for the requested indication):
   1. Anemia defined as mean hemoglobin (Hb) level below the testing laboratory’s lower limit of the normal range based on age and gender OR
   2. Thrombocytopenia (platelet count less than 100,000/microliter on at least 2 measurements) OR
   3. Hepatomegaly OR
   4. Splenomegaly OR
   5. Growth failure (i.e., growth velocity is below the standard mean for age) OR
   6. Evidence of bone disease with other causes ruled out AND
7. If the requested agent is Cerdelga or eliglustat, the patient is a CYP2D6 extensive metabolizer (EM), intermediate metabolizer (IM), or poor metabolizer (PM), as detected by an FDA-cleared test for determining CYP2D6 genotype AND
8. If the requested agent is Zavesca or miglustat, enzyme replacement therapy (ERT) is NOT a therapeutic option (e.g., due to allergy, hypersensitivity, poor venous access, previous ERT failure) AND
9. If the request is for one of the following brand agents with an available generic equivalent (listed below), then ONE of the following:
   1. The patient has an intolerance or hypersensitivity to the generic equivalent that is not expected to occur with the brand agent OR
   2. The patient has an FDA labeled contraindication to the generic equivalent that is not expected to occur with the brand agent OR
   3. The prescriber has provided information to support the use of the requested brand agent over the generic equivalent AND

10. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., endocrinologist, geneticist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
11. The patient will NOT be using the requested agent in combination with another substrate reduction therapy agent (e.g., Cerdelga, Zavesca) for the requested indication AND
12. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval:  12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process AND
2. The patient has had improvements or stabilization with the requested agent as indicated by ONE of the following:
   1. Spleen volume OR
   2. Hemoglobin level OR
   3. Liver volume OR
   4. Platelet count (sufficient to decrease the risk of bleeding) OR
   5. Growth OR
   6. Bone pain or crisis AND
3. If the request is for one of the following brand agents with an available generic equivalent (listed below), then ONE of the following:
   1. The patient has an intolerance or hypersensitivity to the generic equivalent that is not expected to occur with the brand agent OR
   2. The patient has an FDA labeled contraindication to the generic equivalent that is not expected to occur with the brand agent OR
   3. The prescriber has provided information to support the use of the requested brand agent over the generic equivalent AND

4. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., endocrinologist, geneticist) or the prescriber has consulted with a specialist in the area of patient’s diagnosis AND
5. The patient will NOT be using the requested agent in combination with another substrate reduction therapy agent (e.g., Cerdelga, Zavesca) for the requested indication AND
6. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval:  12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Target Agent(s) will be approved when ONE of the following is met:

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. ALL of the following:
   1. The requested quantity (dose) is greater than the program quantity limit AND
   2. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
   3. The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit OR
3. ALL of the following:
   1. The requested quantity (dose) is greater than the program quantity limit AND
   2. The requested quantity (dose) is greater than the maximum FDA labeled dose for the requested indication AND
   3. The prescriber has provided information in support of therapy with a higher dose for the requested indication

Length of Approval: 12 months